Wolfram syndrome is a rare autosomal recessive disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (also known as DIDMOAD). Insulin dependent diabetes usually occurs as the initial manifestation during the first decade of life, while the diagnosis of Wolfram syndrome is invariably later with onset of the other features in the second and ensuing decades. Two causative genes for this genetic disorder have been identified and are named WFS1 and WFS2. It has been shown that multiple mutations in the WFS1 gene, as well as a specific mutation in the WFS2 gene, lead to β cell death and neurodegeneration through endoplasmic reticulum (ER) and mitochondrial dysfunction. WFS1 gene variants are also associated with a risk of type 2 diabetes. Moreover, a specific WFS1 variant can cause autosomal dominant diabetes.
Wolfram syndrome is caused by stress in the ER, a cell component involved in many vital functions of the eyes, brain, and pancreas. The ER is a membrane-bound organelle that is crucial for the folding and maturation of proteins, lipid biosynthesis, and homeostasis of intracellular Ca2+ and reduction-oxidation (redox) potential. Protein folding and modification in the ER is highly sensitive to disturbances of ER homeostasis, including altered glycosylation, ER Ca2+ depletion, increased mRNA translation, oxidative stress, energy deprivation, metabolic challenge, and inflammatory stimuli. The accumulation of unfolded and misfolded proteins in the ER lumen, termed ER stress, activates intracellular signaling pathways to resolve the protein folding defect. This unfolded protein response (UPR) increases the capacity of ER protein folding and modification, reduces global protein synthesis, and activates ER-associated protein degradation (ERAD). If ER stress is too severe or chronic, or the UPR is compromised and not able to restore the protein folding homeostasis, numerous apoptotic signaling pathways are activated.
Despite the underlying importance of ER malfunction in ER stress disorders such as Wolfram syndrome and the identification of WFS1 and WFS2 genes, a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Thus, to date there are no known treatments for Wolfram Syndrome and other ER stress disorders.